The pressure-derived microvascular resistance reserve and its correlation to Doppler MRR measurement-a proof of concept study.

Background: Microvascular resistance reserve (MRR) is a recently introduced specific index of coronary microcirculation. MRR calculation can utilize parameters deriving from coronary flow reserve (CFR) assessment, provided that intracoronary pressure data are also available. The previously proposed pressure-bounded CFR (CFRpb) defines the possible CFR interval on the basis of resting and hyperemic pressure gradients in the epicardial vessel, however, its correlation to the Doppler wire measurement was reported to be rather poor without the correction for hydrostatic pressure. Purpose: We aimed to determine the pressure-bounded coronary MRR interval with hydrostatic pressure correction according to the previously established equations of CFRpb adapted for the MRR concept. Furthermore, we also aimed to design a prediction model using the actual MRR value within the pressure-bounded interval and validate the results against the gold-standard Doppler wire technique. Methods: Hydrostatic pressure between the tip of the catheter and the sensor of the pressure wire was calculated by height difference measurement from a lateral angiographic view. In the derivation cohort the pressure-bounded MRR interval (between MRRpbmin and MRRpbmax) was determined solely from hydrostatic pressure-corrected intracoronary pressure data. The actual MRR was calculated by simple hemodynamic equations incorporating the anatomical data of the three-dimensionally reconstructed coronary artery (MRRp-3D). These results were analyzed by regression analyses to find relations between the MRRpb bounds and the actual MRRp-3D. Results: In the derivation cohort of 23 measurements, linear regression analysis showed a tight relation between MRRpbmax and MRRp-3D (r 2 = 0.74, p < 0.0001). Using this relation (MRRp-3D = 1.04 + 0.51 × MRRpbmax), the linear prediction of the MRR was tested in the validation cohort of 19 measurements against the gold standard Doppler wire technique. A significant correlation was found between the linearly predicted and the measured values (r = 0.54, p = 0.01). If the area stenosis (AS%) was included to a quadratic prediction model, the correlation was improved (r = 0.63, p = 0.004). Conclusions: The MRR can be predicted reliably to assess microvascular function by our simple model. After the correction for hydrostatic pressure error, the pressure data during routine FFR measurement provides a simultaneous physiological assessment of the macro- and microvasculature.

Simplified coronary flow reserve calculations based on three-dimensional coronary reconstruction and intracoronary pressure data.

BACKGROUND: Measurements of fractional flow reserve (FFR) and/or coronary flow reserve (CFR) are widely used for hemodynamic characterization of coronary lesions. The frequent combination of the epicardial and microvascular disease may indicate a need for complex hemodynamic evaluation of coronary lesions. This study aims at validating the calculation of CFR based on a simple hemodynamic model to detailed computational fluid dynamics (CFD) analysis. METHODS: Three-dimensional (3D) morphological data and pressure values from FFR measurements were used to calculate the target vessel. Nine patients with one intermediate stenosis each, measured by pressure wire, were included in this study. RESULTS: A correlation was found between the determined CFR from simple equations and from a steady flow simulation (r = 0.984, p < 10-5). There was a significant correlation between the CFR values calculated by transient and steady flow simulations (r = 0.94, p < 10-3). CONCLUSIONS: Feasibility was demonstrated of a simple hemodynamic calculation of CFR based on 3D-angiography and intracoronary pressure measurements. A simultaneous determination of both the FFR and CFR values provides the capability to diagnose microvascular dysfunction: the CFR/FFR ratio characterizes the microvascular reserve.

Novel Method to Detect Pitfalls of Intracoronary Pressure Measurements by Pressure Waveform Analysis.

Potential pitfalls of fractional flow reserve (FFR) measurements are well-known drawbacks of invasive physiology measurement, e.g., significant drift of the distal pressure trace may lead to the misclassification of stenoses. Thus, a simultaneous waveform analysis of the pressure traces may be of help in the quality control of these measurements by online detection of such artefacts as the drift or the wedging of the catheter. In the current study, we analysed the intracoronary pressure waveform with a dedicated program. In 130 patients, 232 FFR measurements were performed and derivative pressure curves were calculated. Local amplitude around the dicrotic notch was calculated from the distal intracoronary pressure traces (δdPn/dt). A unidimensional arterial network model of blood flow was employed to simulate the intracoronary pressure traces at different flow rates. There was a strong correlation between δdPn/dt values measured during hyperaemia and FFR (r = 0.88). Diagnostic performance of distal δdPn/dt ≤ 3.52 for the prediction of FFR ≤ 0.80 was 91%. The correlation between the pressure gradient and the corresponding δdPn/dt values obtained from all measurements independently of the physiological phase was also significant (r = 0.80). During simulation, the effect of flow rate on δdPn/dt further supported the close correlation between the pressure ratios and δdPn/dt. Discordance between the FFR and the δdPn/dt can be used as an indicator of possible technical problems of FFR measurements. Hence, an online calculation of the δdPn/dt may be helpful in avoiding some pitfalls of FFR evaluation.

Pressure- and 3D-Derived Coronary Flow Reserve with Hydrostatic Pressure Correction: Comparison with Intracoronary Doppler Measurements.

Purpose: To develop a method of coronary flow reserve (CFR) calculation derived from three-dimensional (3D) coronary angiographic parameters and intracoronary pressure data during fractional flow reserve (FFR) measurement. Methods: Altogether 19 coronary arteries of 16 native and 3 stented vessels were reconstructed in 3D. The measured distal intracoronary pressures were corrected to the hydrostatic pressure based on the height differences between the levels of the vessel orifice and the sensor position. Classical fluid dynamic equations were applied to calculate the flow during the resting state and vasodilatation based on morphological data and intracoronary pressure values. 3D-derived coronary flow reserve (CFRp-3D) was defined as the ratio between the calculated hyperemic and the resting flow and was compared to the CFR values simultaneously measured by the Doppler sensor (CFRDoppler). Results: Haemodynamic calculations using the distal coronary pressures corrected for hydrostatic pressures showed a strong correlation between the individual CFRp-3D values and the CFRDoppler measurements (r = 0.89, p < 0.0001). Hydrostatic pressure correction increased the specificity of the method from 46.1% to 92.3% for predicting an abnormal CFRDoppler < 2. Conclusions: CFRp-3D calculation with hydrostatic pressure correction during FFR measurement facilitates a comprehensive hemodynamic assessment, supporting the complex evaluation of macro-and microvascular coronary artery disease.

Anatomical Assessment vs. Pullback REsting full-cycle rAtio (RFR) Measurement for Evaluation of Focal and Diffuse CoronarY Disease: Rationale and Design of the "READY Register".

Background: The morphology and functional severity of coronary stenosis show poor correlation. However, in clinical practice, the visual assessment of the invasive coronary angiography is still the most common means for evaluating coronary disease. The fractional flow reserve (FFR), the coronary flow reserve (CFR), and the resting full-cycle ratio (RFR) are established indices to determine the hemodynamic significance of a coronary stenosis. Design/Methods: The READY register (NCT04857762) is a prospective, multicentre register of patients who underwent invasive intracoronary FFR and RFR measurement. The main aim of the registry is to compare the visual estimate of coronary lesions and the functional severity of the stenosis assessed by FFR, as well as the RFR pullback. Characterizations of the coronary vessel for predominantly focal, diffuse, or mixed type disease according to visual vs. RFR pullback determination will be compared. The secondary endpoint of the study is a composite of major adverse cardiac events, including death, myocardial infarction, and repeat coronary revascularization at 1 year. These endpoints will be compared in patients with non-ischemic FFR in the subgroup of cases where the local pressure drop indicates a focal lesion according to the definition of ΔRFR > 0.05 (for <25 mm segment length) and in the subgroup without significant ΔRFR. In case of an FFR value above 0.80, an extended physiological analysis is planned to diagnose or exclude microvascular disease using the CFR/FFR index. This includes novel flow dynamic modeling for CFR calculation (CFRp-3D). Conclusion: The READY register will define the effect of RFR measurement on visual estimation-based clinical decision-making. It can identify a prognostic value of ΔRFR during RFR pullback, and it would also explore the frequency of microvascular disease in the patient population with FFR > 0.80. Clinical Trial Registration: ClinicalTrials.gov (NCT04857762).

The Holistic Coronary Physiology Display: Calculation of the Flow Separation Index in Vessel-Specific Individual Flow Range during Fractional Flow Reserve Measurement Using 3D Coronary Reconstruction.

In order to make optimal decisions on the treatment of atherosclerotic coronary heart disease (CHD), appropriate evaluation is necessary, including both the anatomical and physiological assessment of the coronary arteries. According to current guidelines, a fractional flow reserve (FFR)-based clinical decision is recommended, but coronary flow reserve (CFR) measurements and microvascular evaluation should also be considered in special cases for a detailed exploration of the coronary disease state. We aimed to generate an extended physiological evaluation during routine FFR measurement and define a new pathological flow-related prognostic factor. Fluid dynamic equations were applied to calculate CFR on the basis of the three-dimensional (3D) reconstruction of the invasively acquired coronary angiogram and the measured intracoronary pressure data. A new, potentially robust prognostic parameter of a coronary lesion called the "flow separation index" (FSi), which is thought to detect the pathological flow amount through a stenosis was introduced in a vessel-specific flow range. Correlations between FSi and the clinically established physiological indices (CFR and FFR) were determined. The FSi was calculated in 19 vessels of 16 patients, including data from the pre- and post-stent revascularization treatment of 3 patients. There was no significant correlation between the FSi and the CFR (r = -0.23, p = 0.34); however, there was significant negative correlation between the FSi and the FFR (r = -0.66, p = 0.002). An even stronger correlation was found between the FSi and the ratio of the resting pressure ratio and the FFR (r = 0.92, p < 0.0001). The diagnostic power of the FSi for predicting the FFR value of <0.80, as a gold standard prognostic factor, was tested by receiver operating characteristic analysis. FSi > 0.022 proved to be the cutoff value of the prediction of a pathologically low FFR with a 0.856 area under the curve (95% confidence interval: 0.620 to 0.972). The present flow-pressure-velocity display provides a comprehensive summary of patient-specific pathophysiology in CHD. The consequences of epicardial stenoses can be evaluated together with their complex relations to microvascular conditions. Based on these values, clinical decision-making concerning both pharmacological therapy and percutaneous or surgical revascularization may be more precisely guided.

The impact of hydrostatic pressure on the result of physiological measurements in various coronary segments.

The effect of hydrostatic pressure on physiological intracoronary measurements is usually ignored in the daily clinical practice. Our aim was to investigate this effect on Pd/Pa (distal/aortic pressure) and FFR (fractional flow reserve). 41 FFR measurements between 0.7 and 0.9 were selected. The difference in the height of the orifice and that of the sensor was defined in mm on the basis of 3D coronary reconstruction. Resting Pd/Pa and FFR were adjusted by subtracting the hydrostatic pressure gradient from the distal pressure. Height measurements were also performed from 2D lateral projections for each coronary segment (n = 305). In case of the LAD, each segment was located higher (proximal: - 13.69 ± 5.4; mid: - 46.13 ± 6.1; distal: - 56.80 ± 7.7 mm), whereas for the CX, each segment was lower (proximal: 14.98 ± 8.3; distal: 28.04 ± 6.3 mm) compared to the orifice. In case of the RCA, the distances from the orifice were much less (proximal: - 6.39 ± 2.9; mid: - 6.86 ± 7.0; distal: 17.95 ± 6.6 mm). The effect of these distances on pressure ratios at 100 Hgmm aortic pressure was between - 0.044 and 0.023. The correction for height differences changed the interpretation of the measurement (negative/positive result) in 5 (12%) and 11 (27%) cases for the FFR (cut-off value at 0.80) and the resting Pd/Pa (cut-off value at 0.92), respectively. The clinical implementation of hydrostatic pressure calculation should be considered during intracoronary pressure measurements. A correction for this parameter may become crucial in case of a borderline significant coronary artery stenosis, especially in distal coronary artery segments.

Three-dimensional evaluation of the spatial morphology of stented coronary artery segments in relation to restenosis.

To investigate the correlations between the three-dimensional (3D) parameters of target coronary artery segments and restenosis after stent implantation. Sixty-four patients after single, cobalt chromium platform stent (27 BM stents and 37 DES) implantation were investigated retrospectively 12 ± 6 months after the index procedure. 3D coronary artery reconstruction was performed before and after the stent implantation using appropriate projections by a dedicated reconstruction software. The curve of the target segment was characterized by the ratio of the vessel length measured at midline (arc: A) and the distance between the edge points of the stent (chord: C): A/C ratio (ACr). Age, diabetes and hyperlipidaemia were taken into account for the statistical evaluation. 22 patients were diagnosed with ISR, while 42 patients without any restenosis served as controls. The two groups did not differ regarding major cardiovascular risk factors, proportion of the treated vessels or the type of stents. Higher initial ACr values were associated with greater straightening of the vessel curvature in all groups (p < 0.001). Significant negative correlations were found in cases of proximal or distal edge bending angles (p < 0.001). Pre-stent edge bending angles < 7° often showed an increase after the stent implantation, while in case of higher initial values, the bending angles generally decreased. Using multivariate logistic regression modelling we found that the pre-stent ACr was an independent predictor of in-stent restenosis (odds ratio for 1% increase of the ACr: 1.08; p = 0.012). Changes of angles at the stent edges following stent implantation correlate with the initial local bending angles. The ACr predispose to chronic shear stress in the vessel wall, which may contribute to the pathological intimal proliferation.

Less invasive fractional flow reserve measurement from 3-dimensional quantitative coronary angiography and classic fluid dynamic equations.

AIMS: The aim of this study was to develop a simplified model of FFR calculation (FFRsim) derived from three-dimensional (3D) coronary angiographic data and classic fluid dynamic equations without using finite element analysis. METHODS AND RESULTS: Intracoronary pressure measurements were performed by pressure wire sensors. The lumens of the interrogated vessel segments were reconstructed in 3D. The coronary artery volumetric flow was calculated based on the velocity of the contrast material. Pressure gradients were computed by classic fluid dynamic equations. The diagnostic power of the simplified computation of the FFR (FFRsim) was assessed by comparing the results with standard invasive FFR measurements (FFRmeas) in 68 vessels with a single stenosis. We found a strong correlation between the FFRsim and the FFRmeas (r=0.86, p<0.0001). The sensitivity and specificity for predicting the abnormal FFR of ≤0.80 (indicating haemodynamically significant stenosis) were 90% and 100%, respectively. The area under the curve (AUC) was 0.96. To achieve 100% negative and positive predictive values we defined the FFRsim >0.88 and the FFRsim ≤0.8 ranges. In our patient population, these ranges were found in 69% of the cases. CONCLUSIONS: According to our simplified model, the invasive FFR measurement can be omitted without misclassification in pre-specified ranges of the calculated FFRsim.

Relationship between reversibility score on corresponding left ventricular segments and fractional flow reserve in coronary artery disease.

OBJECTIVE: The objective of this study was to find the correlation between the severity of perfusion abnormality detected by scintigraphy and the FFR value, as well as the localization of a particular coronary lesion. On the basis of FFR values and the corresponding left ventricular segments, we proposed a combined index to aim for better correlation with myocardial ischemia than the FFR parameter alone. METHODS: Twenty-eight patients (male: 22, female: 6, age 62±7.62) having FFR measurements and myocardial perfusion SPECT studies were enrolled in our retrospective analysis. FFR measurements on 36 vessels (20 LAD, 6 LCx, 10 RCA) with intermediate stenosis (40%-60%) were compared to the Tc-99m SestaMIBI myocardial perfusion SPECT studies. SPECT studies were performed before the invasive procedure in all cases. We introduced a new ischemic index, the left ventricular ischemic index (LVIi), by combining FFR values with the number of corresponding myocardial segments (N) [LVIi=N x (1-FFR)]. This index correlated with the regional myocardial perfusion defects identified on the scintigrams. A perfusion reversibility score of 2 or above was considered indicative of active ischemia (regional difference score: rDSc). For the statistical analysis, we used linear regression analysis and receiver operating characteristic (ROC) curve analysis to compare the different parameters. RESULTS: A close linear relationship was found between the LVIi and rDSc values (p<0.001) with linear regression analysis. When analyzing all FFR values independently of the localization of the lesions, they also correlated significantly to the rDSc, but this relation was not as close. LVIi predicted active ischemia (≥2 rDSc) on myocardial scintigraphy with 78% sensitivity and 94% specificity when the cutoff value was set to 0.96. FFR alone predicted ischemia on scintigraphy with 72% sensitivity and 94% specificity at the best 0.8 cut-off value. The area under the ROC curve was significantly higher for LVIi than FFR (0.94 vs. 0.87; p<0.05). CONCLUSION: The scintigraphic data indicate that an LVIi >0.96 implies a clinically relevant stenotic lesion. In our opinion, FFR values, weighted with the corresponding left ventricular segments, should be taken into consideration for the best clinical decision-making.

Fractional flow reserve calculation from 3-dimensional quantitative coronary angiography and TIMI frame count: a fast computer model to quantify the functional significance of moderately obstructed coronary arteries.

OBJECTIVES: This study sought to present a novel computer model for fast computation of myocardial fractional flow reserve (FFR) and to evaluate it in patients with intermediate coronary stenoses. BACKGROUND: FFR is an indispensable tool to identify individual coronary stenoses causing ischemia. Calculation of FFR from x-ray angiographic data may increase the utility of FFR assessment. METHODS: Consecutive patients with intermediate coronary stenoses undergoing pressure wire-based FFR measurements were analyzed by a core laboratory. Three-dimensional quantitative coronary angiography (QCA) was performed and the mean volumetric flow rate at hyperemia was calculated using TIMI (Thrombolysis In Myocardial Infarction) frame count combined with 3-dimensional QCA. Computational fluid dynamics was applied subsequently with a novel strategy for the computation of FFR. Diagnostic performance of the computed FFR (FFRQCA) was assessed using wire-based FFR as reference standard. RESULTS: Computation of FFRQCA was performed on 77 vessels in 68 patients. Average diameter stenosis was 46.6 ± 7.3%. FFRQCA correlated well with FFR (r = 0.81, p < 0.001), with a mean difference of 0.00 ± 0.06 (p = 0.541). Applying the FFR cutoff value of ≤0.8 to FFRQCA resulted in 18 true positives, 50 true negatives, 4 false positives, and 5 false negatives. The area under the receiver-operating characteristic curve was 0.93 for FFRQCA, 0.73 for minimum lumen area, and 0.65 for percent diameter stenosis. CONCLUSIONS: Computation of FFRQCA is a novel method that allows the assessment of the functional significance of intermediate stenosis. It may emerge as a safe, efficient, and cost-reducing tool for evaluation of coronary stenosis severity during diagnostic angiography.